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Chronic pain is a prevalent health condition that imposes a significant burden on the global health system. Health literacy is a determinant of the quality of pain management which directly impacts public and individual health. However, the existing health literacy measurements have predominantly focused on medical models stemmed from Western culture and the knowledge of non-Western health models has largely been neglected. This review scopes refereed health literacy publications with regard to traditional Chinese medicine and chronic pain to explore and identify 1) the conceptual basis underlying the development of traditional Chinese medicine health literacy in this area, and 2) measurement tools used in this area and their associated psychometric qualities. Twenty-eight journal articles were assessed and the results showed that most studies' conceptual frameworks were unable to cover three key health literacy aspects defined by the World Health Organization (access, understand, and apply). Furthermore, the identified health literacy measurement tools generally lacked rigorous psychometric evaluation. Future studies should focus on exploring a comprehensive model that encompasses various health models and developing measurement tools with more culturally representative psychometric assessments., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Navigating the duality of opioids' potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model. We found that chronic morphine treatment increases FLT3 and MOR co-expression, and that inhibiting FLT3 represses MOR-induced hyperactivation of the cyclic adenosine monophosphate (cAMP) signaling pathway, mitigating maladaptive excitatory processes engaged after chronic morphine treatment. Furthermore, in postsurgical or inflammatory models of chronic pain, co-administering morphine with a FLT3-specific inhibitor not only prevents or suppresses tolerance and hyperalgesia but also potentiates the analgesic efficacy of morphine, without aggravating other morphine-induced adverse effects. Our findings suggest that pairing morphine with FLT3 inhibitors could become a promising avenue for chronic pain management to safely harness the power of opioids, without the risk of dose escalation. By enhancing morphine analgesic potency through FLT3 inhibition, this approach could minimize opioid dosage, thereby curtailing the risk of addiction and other opioid-related side effects., (© 2024. The Author(s).)

Purpose: This study evaluated the effectiveness of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) treatments using multiple pharmaceutical agents that could simultaneously preserve or enhance fertility capability., Materials and Methods: This was a single-center-based, randomized controlled study, whereas the final analysis evaluated a total 350 CP/CPPS patients (age range, 28-40 years) and 50 patients were randomly allocated to each therapeutic group, with a 1:1 ratio. The therapeutic groups consist of tadalafil (group 1, 5 mg daily), L-carnitine (group 2, 2 g daily), Serenoa repens extract (group 3, 320 mg daily), group 4 (tadalafil+L-carnitine), group 5 (tadalafil+ S. repens ), group 6 (L-carnitine+ S. repens ), and group 7 (tadalafil+L-carnitine+ S. repens ). The treatment outcomes at 3 months post-therapy were analyzed., Results: At 3 months post-therapy, the mean total sperm motility was significantly improved in all groups. A normal morphology improvement was observed in L-carnitine receiving groups. The mean total score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the mean International Prostate Symptom Score (IPSS) showed the greatest reduction in intensity in group 7. Logistic regression analyses showed that group 5 and group 7 were significantly associated with improvements in total IPSS and total NIH-CPSI scores at 3 months post-therapy. Group 7 was a significant predictor for improving total sperm motility, leukocytospermia and normal form of sperm., Conclusions: Tadalafil, carnitine, and S. repens combination therapy could be considered a feasible treatment option for CP/CPPS males with subfertility., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

Researchers call for better education and supervision to prevent negative effects., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This systematic review and meta-analysis aimed to inventory all outcome measures that are affected by tapering in chronic noncancer pain and to investigate the effectiveness of tapering., Methods: A literature search was conducted from inception to April 2024 in MEDLINE via PubMed, Web of Science, SCOPUS, EMBASE, and PsycINFO., Results: The initial database search identified 3969 articles, which were screened by two independent reviewers. Studies evaluating pain medication tapering in adults with chronic noncancer pain were eligible for inclusion. In total, 57 and 34 articles were included in the systematic review and meta-analysis, respectively. Risk of bias assessment demonstrated poor, fair, and good quality in 30, 24, and three studies, respectively. Pain intensity was the most reported outcome measure, as reported in 28 studies. Furthermore, a random-effect three-level meta-analysis was performed. An overall effect size of 0.917 (95% confidence interval 0.61-1.22; P<0.001) was found, indicating a beneficial effect of tapering. In addition, a statistically significant improvement was demonstrated after tapering for pain intensity, headache disability, the number of headache days per month, anxiety, depression, the number of pills consumed per month, the number of days with medication intake per month, pain catastrophising, and pain interference. No statistically significant effect was observed for physical functioning, mental health-related quality of life, opioid use, pain self-efficacy, and physical health-related quality of life., Conclusions: This systematic review revealed a broad range of outcome measures affected by tapering. Owing to the high risk of bias of the included articles, the results of this meta-analysis must be interpreted with caution., Systematic Review Protocol: CRD42023416343 (PROSPERO)., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Abstract: Chronic ocular pain (COP) is a leading cause of eye care visits in the US and has a substantial impact on quality of life and visual functioning. Although many conditions underlie COP, such as dry eye disease or post-herpetic neuralgia, some people experience pain without significant ocular signs on examination or known risk factors (eg, traumatic injury). Antidepressant medications that act primarily on the central nervous system, such as tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors, are often used to treat patients with COP, but a recent Cochrane review and network meta-analysis investigating 25 different antidepressants concluded that only two serotonin and norepinephrine reuptake inhibitors, have sufficient data to support their use in chronic pain. For all other medications, the evidence was of low certainty. We contend that while these medications are not a cure-all for chronic pain or COP, it is premature to conclude that these medications have no role in their treatment. We provide a rationale for continued use of antidepressant medications as part of a multimodal targeted treatment for patients with COP., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Long-term opioid use is related to numerous harms and has uncertain efficacy for chronic, non-cancer pain. Identification of individuals at risk for long-term opioid use can help support treatment decisions. The aim of this study was to determine psychosocial factors associated with opioid use 6 months after a work-related injury., Methods: This was a prospective observational cohort study incorporating surveys and administrative data. Eligibility included a workers' compensation claim for an injury between June 2019 and September 2021, no opioid use within 3 months before injury, and opioid use within 6 weeks after injury. The outcome was self-reported opioid use at the 6-month follow-up survey (no use, use some days, or use most or every day). Multinomial logistic regression models were used to calculate relative risk ratios (RRRs) for associations between self-reported psychosocial factors and long-term opioid use., Results: Of the 1724 respondents, 301 (17.5%) reported taking long-term opioids on some days and 87 (5.0%) reported taking long-term opioids on most or every day. After adjustment for sociodemographic and clinical covariates, workers reporting work fear-avoidance had a higher relative risk of opioid use most or every day, versus no opioid use at the 6-month survey, compared to those without work fear-avoidance (RRR = 1.95, 95% CI = 1.08, 3.50). Anxiety symptoms, depression symptoms, and recovery expectations were not associated with long-term opioid use after covariate adjustment., Conclusions: Work fear-avoidance was associated with long-term opioid use in this study of injured workers. Addressing fears surrounding an injury and returning to work may help deter reliance on long-term opioids., (© 2024 Wiley Periodicals LLC.)

Chronic pain, which affects more than one-third of the world's population, represents one of the greatest medical challenges of the 21st century, yet its effective management remains sub-optimal. The 'gold standard' for the treatment of moderate to severe pain consists of opioid ligands, such as morphine and fentanyl, that target the µ-opioid receptor (MOP). Paradoxically, these opioids also cause serious side effects, including constipation, respiratory depression, tolerance, and addiction. In addition, the development of opioid-use disorders, such as opioid diversion, misuse, and abuse, has led to the current opioid crisis, with dramatic increases in addiction, overdoses, and ultimately deaths. As pain is a complex, multidimensional experience involving a variety of pathways and mediators, dual or multitarget ligands that can bind to more than one receptor and exert complementary analgesic effects, represent a promising avenue for pain relief. Indeed, unlike monomodal therapeutic approaches, the modulation of several endogenous nociceptive systems can often result in an additive or even synergistic effect, thereby improving the analgesic-to-side-effect ratio. Here, we provide a comprehensive overview of research efforts towards the development of dual- or multi-targeting opioid/nonopioid hybrid ligands for effective and safer pain management. We reflect on the underpinning discovery rationale by discussing the design, medicinal chemistry, and in vivo pharmacological effects of multitarget antinociceptive compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Opioid abuse and mortality are ravaging American society, highlighting the need to find alternative effective analgesics with fewer side effects. FDA-approved topical analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat musculoskeletal pain but can cause adverse effects. Natural compounds, including essential oils, are potential therapeutic alternatives for managing musculoskeletal pain. If these compounds can provide comparable analgesia to FDA-approved products, it will increase the available options for people with pain, improving quality of life with minimal morbidity and mortality., Objective: This study assesses the effectiveness and onset of action of Bonipar, a topical analgesic formulated with camphor, methyl salicylate, and oils of coconut, eucalyptus, nutmeg, and rosemary, in managing musculoskeletal pain compared to 1.5 % diclofenac solution, an FDA-approved topical non-steroidal anti-inflammatory drug., Methods: One hundred sixty-four adult patients with localized musculoskeletal pain were randomly assigned to twice-daily applications of either Bonipar or Diclofenac for one week. The primary outcome measure was a 50 % reduction in pain after one week. Secondary outcomes included the change in pain from baseline and onset of action, defined as the first reduction in pain by 20 %., Results: All patients completed the initial pain assessment to determine the onset of action. One-week data was available for 74 patients treated with diclofenac and 72 patients treated with Bonipar. Data for 18 patients were incomplete. The proportion of patients achieving a 50 % reduction in pain was statistically similar between the two groups. The success rates of achieving a 50 % pain reduction with Bonipar were found to be non-inferior to those treated with diclofenac. All follow-up time points showed roughly similar results between the groups. Regression models adjusted for age and sex revealed no significant effects on pain changes. Secondary analyses demonstrated no significant differences between the groups., Discussion: The topical analgesic Bonipar demonstrates a comparable onset of action, with efficacy non-inferior to diclofenac in the management of musculoskeletal pain, while showing fewer adverse effects compared to diclofenac. These findings highlight the potential of Bonipar as a valuable alternative for the treatment of localized pain., (Published by Elsevier Ltd.)

Long-term inflammation can cause chronic pain and trigger patients' anxiety by sensitizing the central nervous system. However, effective drugs with few side effects for treating chronic pain-induced anxiety are still lacking. The anxiolytic and anti-inflammatory effects of ruscogenin (RUS), an important active compound in Ophiopogon japonicus, were evaluated in a mouse model of chronic inflammatory pain and N9 cells. RUS (5, 10, or 20 mg/kg/day, i.g.) was administered once daily for 7 days after CFA injection; pain- and anxiety-like behaviors were assessed in mice. Anti-inflammatory effect of RUS (0.1, 1, 10 μM) on N9 microglia after LPS treatment was evaluated. Inflammatory markers (TNF-α, IL-1β, IL-6, CD86, IL-4, ARG-1, and CD206) were measured using qPCR. The levels of IBA1, ROS, NF-κB, TLR4, P-IKK, P-IκBα, and P65, MAPKs (ERK, JNK, and P38), NLRP3 (caspase-1, ASC, and NLRP3) were detected by Western blotting or immunofluorescence staining. The potential target of RUS was validated by molecular docking and adeno-associated virus injection. Mice in CFA group exhibited allodynia and anxiety-like behaviors. LPS induced neuroinflammation in N9 cells. Both CFA and LPS increased the levels of IBA1, ROS, and inflammatory markers. RUS (10 mg/kg in vivo and 1 μM in vitro) alleviated these alterations through NF-κB/MAPKs/NLRP3 signaling pathways but had no effect on pain hypersensitivity. TLR4 strongly interacted with RUS, and TLR4 overexpression abolished the effects of RUS on anxiety and neuroinflammation. RUS exerts anti-inflammatory and anxiolytic effects via TLR4-mediated NF-κB/MAPKs/NLRP3 signaling pathways, which provides a basis for the treatment of chronic pain-induced anxiety., (© 2024 John Wiley & Sons, Ltd.)

Background: Chronic non-specific low back pain (CNSLBP) lacks identifiable anatomical pathology and effective pharmacological treatment. Alternative approaches in homeopathy, specifically clinical homeopathy, utilize ultra-diluted (potentized) biological products. In Brazil, standardized biotherapics from sheep tissues, particularly fifty-millesimal (LM) potencies of sheep Lumbar Vertebra , have shown promise in alleviating CNSLBP., Objectives: Our objective is to present the study protocol of a clinical trial that will assess the efficacy and safety of the biotherapic Lumbar Vertebra LM2 in the short-term management of CNSLBP and to estimate its therapeutic duration., Methods: A randomized, double-blind, crossover, placebo-controlled clinical trial spanning 8 weeks per participant was designed. Participants will include 120 individuals (aged 20 to 60 years) with clinically diagnosed CNSLBP by the study's physiotherapist. Exclusion criteria are radicular pain, signs of radiculopathy, specific lumbar spine disorders, pregnancy, or puerperium (up to 60 days after delivery). The medical intervention includes participants being randomly assigned to one of two treatment sequences: homeopathy-placebo or placebo-homeopathy. The treatments will consist of Lumbar Vertebra LM2 oral solution, topical cream, and indistinguishable placebos. Each treatment period will span 2 weeks, with a 4-week washout interval between them. Primary outcome is the assessment of changes in self-reported pain levels using the numeric rating scale (NRS) score, analyzed with a random effects model across both treatment periods. Secondary outcomes are assessment of changes in self-reported disability levels using the Oswestry Disability Index (ODI), analyzed with a random effects model across both treatment periods, and pain and disability variations, evaluated by the NRS score and ODI respectively, after the first and second treatment periods. Adverse events will be assessed at weeks 2 and 8. Pain medications will be used concomitantly. Adherence will be evaluated by the weight of medication returned/standard weight., Discussion: The BIOVERT (Bioactive Vertebra) trial protocol is designed to investigate a homeopathic strategy for short-term CNSLBP treatment. Favorable outcomes for homeopathy could prompt subsequent studies evaluating the long-term effectiveness of LM potencies of Lumbar Vertebra for CNSLBP., Trial Registration: UMIN Clinical Trials Registry - ID: UMIN000051957., Competing Interests: None declared., (Faculty of Homeopathy. This article is published by Thieme.)

Background and Aims: Chronic non-cancer pain (CNCP) is one of the most common causes of disability globally. Opioid prescribing to treat CNCP remains widespread, despite limited evidence of long-term clinical benefit and evidence of harm such as problematic pharmaceutical opioid use (POU) and overdose. The study aimed to measure the prevalence of POU in CNCP patients treated with opioid analgesics., Method: A comprehensive systematic literature review and meta-analysis was undertaken using MEDLINE, Embase and PsycINFO databases from inception to 27 January 2021. We included studies from all settings with participants aged ≥ 12 with non-cancer pain of ≥ 3 months duration, treated with opioid analgesics. We excluded case-control studies, as they cannot be used to generate prevalence estimates. POU was defined using four categories: dependence and opioid use disorder (D&OUD), signs and symptoms of D&OUD (S&S), aberrant behaviour (AB) and at risk of D&OUD. We used a random-effects multi-level meta-analytical model. We evaluated inconsistency using the I 2 statistic and explored heterogeneity using subgroup analyses and meta-regressions., Results: A total of 148 studies were included with > 4.3 million participants; 1% of studies were classified as high risk of bias. The pooled prevalence was 9.3% [95% confidence interval (CI) = 5.7-14.8%; I 2  = 99.9%] for D&OUD, 29.6% (95% CI = 22.1-38.3%, I 2  = 99.3%) for S&S and 22% (95% CI = 17.4-27.3%, I 2  = 99.8%) for AB. The prevalence of those at risk of D&OUD was 12.4% (95% CI = 4.3-30.7%, I 2  = 99.6%). Prevalence was affected by study setting, study design and diagnostic tool. Due to the high heterogeneity, the findings should be interpreted with caution., Conclusions: Problematic pharmaceutical opioid use appears to be common in chronic pain patients treated with opioid analgesics, with nearly one in 10 experiencing dependence and opioid use disorder, one in three showing signs and symptoms of dependence and opioid use disorder and one in five showing aberrant behaviour., (© 2024 The Author(s). Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Chronic pain, pain persisting longer than six months, afflicts 20% of the U.S. population and is the leading cause of disability. To manage pain, many chronic pain patients (CPPs) and healthcare providers turn to opioids, prescription medications that block pain signals and offer relief. However, in light of the U.S.' ongoing opioid epidemic, CPPs without a history of opioid use disorder (OUD) are facing increased stigma when seeking opioid medication. Further, many have been forced to taper their therapeutic dose due to updated Centers for Disease Control and Prevention prescribing guidelines in 2016 and 2022, with a range of (adverse) outcomes. Though research has explored experiences of chronic pain and OUD independently, few studies have explored how media coverage of the opioid epidemic has shaped representations, and resulting stereotypes, of CPPs. Guided by framing theory, this content analysis examines sources' characterization of CPPs amidst a decade of U.S. news coverage of the opioid epidemic ( N  = 492). Findings identify four dominant news frames, including two novel frames termed culpability and strategy , and elements (i.e., characters, significant events) that comprise these frames. When discussed, CPPs were ascribed the identity of a drug-seeking addict 82% of the time. Collectively, this study provides insight as to how news media coverage of the opioid epidemic influence(d) public perceptions of chronic pain (patients). Findings offer theoretical and practical implications for media outlets, policymakers, CPPs and healthcare providers, as well as highlighting how use of opioids for pain management does not equate to abuse of opioids.

Background: Some have advocated that nabilone be used rather than opioids to manage chronic, noncancer pain, since the former drug may have a better safety profile., Objective: We compared the safety of incident nabilone use relative to incident opioid use with respect to multiple clinically important outcomes., Design: A population-based, retrospective cohort study., Setting: Province of Ontario, Canada., Participants: Persons aged 12 years and older, diagnosed with a musculoskeletal condition within the past 3 years prior to the index date., Exposures: Incident nabilone use, with incident opioid use serving as the reference group., Measurements: Within 3 months following the index date, we separately evaluated for pneumonia, motor vehicle accidents, falls or fractures, mental and behavioral disorder due to psychoactive substance use, and all-cause mortality., Results: A total of 18,863 incident nabilone users were propensity score matched to an equal number of opioid users. In the overall matched analysis, incident nabilone users vs. incident opioid users had significantly lower rates of pneumonia (hazard ratio [HR] 0.78, 95% CI 0.63-0.96), falls or fractures (HR 0.56, 95% CI 0.50-0.64), and all-cause mortality (HR 0.79, 95% CI 0.65-0.95), but significantly higher rate of mental or behavioral disorder (HR 2.23, 95% CI 1.45-3.43). There was no significant difference between groups with respect to rate of motor vehicle accidents., Limitations: Unmeasured confounding may have influenced results., Conclusions: While usage of nabilone relative to opioids was associated with reduced rates of pneumonia, falls or fractures, and all-cause mortality, it was simultaneously associated with an increased rate of adverse mental health outcomes. This picture of mixed safety results raises concerns with the policy approach of broadly substituting use of opioids with nabilone., Funding Source: Ontario Ministry of Health., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Abstract: Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa . A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain. We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A 2A receptor (A 2A R) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A 2A R to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A 2A R agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity., (Copyright © 2024 International Association for the Study of Pain.)

Objectives: A substantial proportion of patients with chronic noncancer pain (CNCP) are treated with tapentadol (TAP) or oxycodone/naloxone (OXN) to improve their perceived physical and mental health over time., Methods: A cross-sectional study was conducted in 135 CNCP outpatients with usual prescribing (TAP: n = 58, OXN: n = 77) at a tertiary-care Spanish Hospital to compare health-related quality-of-life (HRQoL) records. Health utility was derived from the EQ-5D-3L. Regression models were performed to search for other HRQoL determinants. Pain intensity, relief, analgesic prescription, adverse events, inpatient stays, emergency department visits, and change to painkiller prescriptions were registered from electronic records., Results: Health utility (0.43 ± 0.24 scores, from -0.654 to 1) was similar for both opioids, although TAP showed a significantly low daily opioid dose requirement, neuromodulators use, and constipation side effect compared with OXN. After multivariable adjustment, the significant predictors of impaired HRQoL were pain intensity (β = -0.227, 95% CI -0-035 to -0.005), number of adverse events (β = -0.201, 95% CI -0.024 to -0.004), and opioid daily dose (β = -0.175, 95% CI -0.097 to -0.012). Male sex (β = -0.044) and pain relief (β = 0.158) should be taken into account for future studies., Conclusions: HRQoL was similar for TAP and OXN in real-world patients with CNCP, albeit with a TAP opioid-sparing effect. More work is needed to explore HRQoL determinants in relation to long-term opioid use in CNCP., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: In Europe, opioid use has surged, largely due to prescriptions for chronic non-malignant pain (CNMP). General practitioners (GPs) and community pharmacists (CPs) play a major role in opioid prescribing for non-malignant pain. Exploring their personal beliefs and practices might reveal underlying mechanisms to identify measures that could halt the further escalation of opioid use., Methods: Guided by the health belief model, a survey was designed and distributed nationwide to examine the practices and beliefs of GPs and CPs in the domains: threats, benefits, barriers and self-efficacy. The results of GPs and CPs were compared at the statement level using chi-square analysis., Results: Of 214 GPs and 212 CPs who completed the survey, the majority agreed that too many opioids are used in the treatment of chronic non-malignant pain (66.8% GPs and 66.5% CPs). Furthermore, they were concerned about the addictive potential of opioids (83.1% GPs and 71.7% CPs). In general, both professions have concerns about opioid use. GPs report a slightly higher degree of self-efficacy and perceive fewer benefits from opioids in treating CNMP. GPs and CPs valued the recommended measures to reduce opioid prescribing, yet less than half actively implement these strategies in their clinics., Conclusion: GPs and CPs believe that opioids are being used too frequently to treat CNMP. However, both professions lack the actions to improve opioid-related care. GPs and CPs require education, collaboration and tools to implement guidelines on non-malignant pain and opioids., Significance: This study, guided by the health belief model, reveals that general practitioners and community pharmacists have serious concerns about opioid use in chronic non-malignant pain. Despite shared concerns, both professions differ in their beliefs about opioid benefits and perceived self-efficacy. Both professions have in common that they value recommended measures to reduce opioid prescribing. Also, they both struggle to implement strategies, emphasizing the urgent need for education, collaboration and tools to align practices with guidelines on non-malignant pain and opioids., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

This study is aimed at exploring the potential mechanisms of melatonin (MT) in treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using network pharmacology and experimental study. The target genes of MT were acquired from the Swiss Target Prediction, SuperPred, SEA, and PharmMapper databases, and the CP/CPPS targets were collected based on OMIM, DisGeNET, and GeneCards databases. The intersection of MT and CP/CPPS target genes was analyzed. A PPI network was constructed using Cytoscape to identify core targets. The shared targets underwent GO and KEGG enrichment analyses by Using R software. Molecular docking of MT with core targets was performed using AutoDock and PyMOL. GROMACS software was used for molecular dynamics simulation. And using cell experiments to verify the potential effect of MT in CP/CPPS. Network pharmacology analysis reveals 284 shared targets between MT and CP/CPPS, with AKT1, SRC, HSP90AA1, PTGS2, BCL2L1, ALB, CASP3, NFKB1, HIF1A, and ESR1 identified as key targets. Enrichment analysis indicates that MT affects CP/CPPS through various biological processes, and pathway analysis emphasizes the significance of PI3K-Akt, MAPK, Ras, FoxO, HIF-1, EGFR, and apoptosis pathways. Molecular docking confirms strong binding between MT and core targets. It is worth noting that the molecular dynamics simulation showed that the average binding free energy of AKT1, PTGS2, ALB, HSP90AA1 proteins, and MT was - 26.15, - 29.48, - 18.59, and - 20.09 kcal/mol, respectively. These results indicated that AKT1, PTGS2, ALB, and HSP90AA1 proteins were strongly bound to MT. Cell experiments demonstrate that MT can inhibit the secretion of IL-1β, IL-6, and TNF-α in LPS-induced RWPE-1 cells, alleviate inflammation, and suppress cell apoptosis and oxidative stress. Network pharmacology, molecular docking, molecular dynamics simulation, and cell experiments showed that MT could play a role in CP/CPPS by regulating multiple targets and pathways. These findings provide an important scientific basis for further exploration of the molecular mechanism and clinical application of MT in CP/CPPS treatment and are expected to provide new ideas and directions for the development of novel therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Humans use cannabinoid drugs to alleviate pain. As cannabis and cannabinoids are legalized in the United States for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain. Here, we tested the effects of repeated ∆ 9 -tetrahydrocannabinol (THC) vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (ie, treated with complete Freund's adjuvant [CFA]). We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA and also reduces mechanical hypersensitivity in CFA males but not females. Many of the antihyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure. We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the cannabinoid type-1 receptor inverse agonist AM251 (1 mg/kg, I.P.) blocks the antihyperalgesic effects of THC vapor in males and females. These data provide a foundation for future work that will explore the cells and circuits underlying the antihyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain. PERSPECTIVE: Cannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals., (Published by Elsevier Inc.)

U.S. adults increasingly report using cannabis to manage chronic pain and rural areas have inadequate comprehensive pain management. Using mixed methods, we aimed to understand how and why some rural adults use cannabis for pain, including within the context of co-use with opioids. Participants (N = 14, Oklahoma) were rural-dwelling adults who used tobacco and ≥1 other substance, including cannabis and opioids, ≥3 days per week. Participants completed 14 days of ecological momentary assessment (EMA) regarding substance use and subsequent in-depth interviews discussing maps of their substance use reports. Half (7/14) described cannabis use for chronic pain, and most of these (85%) reported use on ≥75% of EMA days. The most frequently reported cannabis use motive was therapeutic/medicinal (90% of use reports). Most reports were of combusted cannabis (88% of use reports) at home (99% of use reports). Same-day use of cannabis and opioids was relatively common (45% of daily surveys), but seemingly not within close temporal proximity. Interview narratives characterized cannabis as modifying pain-adjacent factors (eg, thoughts), not eliminating pain itself. They recounted using a repertoire of substances to manage different pain dimensions (eg, intensity, quality) and balance perceived trade-offs of different substances. Participants described high medical cannabis access, low pain specialist access, and most physicians as unwilling to discuss cannabis for pain. The findings suggest that rural-dwelling patients could benefit from increased access to comprehensive pain management, having cannabis addressed within pain management provider discussions, and that risks and benefits of cannabis use for pain must be better established. PERSPECTIVE: This study used a geographically explicit EMA mixed method to gather rich, intensive pilot data on cannabis use and co-use for chronic pain in rural Oklahoma. It provides unique insights to inform future research on cannabis use among a vulnerable and understudied subgroup of adults with pain-rural residents., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

PURPOSE OF REVIEW: The purpose of this narrative review is to evaluate the efficacy of the most commonly studied intradiscal biologics used for the treatment and alleviation of chronic intractable discogenic low back pain. Additionally, it explores the therapeutic potential and durability of these novel treatment options. RECENT FINDINGS: Recently published literature highlights the therapeutic potential of intradiscal biologics, such as mesenchymal stem cells, platelet-rich plasma, and alpha-2-macroglobulin, in promoting chondrogenesis within the lumbar intervertebral discs to treat discogenic low back pain. Studies demonstrate significant improvements in pain relief, physical function, and quality of life post-treatment. A comprehensive review of the literature evaluating the efficacy of intradiscal biologics suggests some evidence supporting its efficacy in treating discogenic low back pain. However, more rigorous studies into mechanistic modulation and large-scale randomized trials as well as a more thorough understanding of adverse events will be instrumental for including these therapies into clinical practice paradigms., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The relief of joint pain is one of the main objectives in the clinical management of arthritis. Although significant strides have been made in improving management of rheumatoid and related forms of inflammatory arthritis, there are still major unmet needs for therapies that selectively provide potent, sustained and safe joint pain relief, especially among patients with osteoarthritis (OA), the most common form of arthritis. We have recently developed ProGel-Dex, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug, which forms a hydrogel upon intra-articular administration and provides sustained improvement in pain-related behavior and inflammation in rodent models of arthritis. The focus of the present study was to investigate the impact of ProGel-Dex formulation parameters on its physicochemical properties and in vivo efficacy. The results of this study provide essential knowledge for the future design of ProGel-Dex that can provide more effective, sustained and safe relief of joint pain and inflammation., Competing Interests: Declaration of competing interest D. Wang, S. R. Goldring, G. Zhao, and X. Wei are co-inventors of a PCT patent application covering ProGel technology. D. Wang and S. R. Goldring hold equity positions in Ensign Pharmaceutical, Inc., a start-up company which has licensed ProGel technology for further preclinical and translational development. The other coauthors declare no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The present study sought to determine the prevalence of chronic non-cancer pain (CNCP) among older adult inpatients with polypharmacy. It also aimed to analyse prescription patterns and assess the therapy adequacy and patient complexity for those with and without CNCP., Methods: This 4-year longitudinal study examined data from an exhaustive acute care hospital register on home-dwelling older adult patients (≥65) with polypharmacy. Commonly known combinations of potentially inappropriate medications were used to estimate therapy adequacy. Patient complexity was evaluated by comparing number of comorbidities and investigating physical and cognitive deficits., Results: We determined a prevalence of CNCP of 9.7% among all older adult inpatients with polypharmacy, rising to 11.3% for those aged ≥85. Overall, CNCP patients were prescribed more drugs and had more comorbidities and physical and cognitive deficits than patients without CNCP. Older adult patients with CNCP received more analgesics, greater quantities of opioids, paracetamol and co-analgesics and elevated opioid dosages. Older adult patients with CNCP aged ≥85 received fewer analgesics, opioids, non-steroidal anti-inflammatory drugs and co-analgesics but more paracetamol. Older adult patients with CNCP were prescribed more potentially inappropriate medications involving opioids. In particular, 24.5% received an opioid and a hypnotic (benzodiazepine or Z-drug), and 8.6% received an opioid and a gabapentinoid., Conclusion: Observed differences in medication use between older adult inpatients with or without CNCP may be relevant for clinical practice. Potentially inadequate co-prescribing (such as hypnotics and opioids) affects a higher proportion of patients with CNCP and may have serious unintended consequences., Significance Statement: This study describes differences in prescription patterns between people with and without chronic non-cancer pain in a large dataset of 20,422 discharges. The differences found may be relevant to clinical practice. In particular, high co-prescribing of opioids and hypnotics may have serious unintended consequences. Greater physical and cognitive deficits may indicate greater patient complexity, and appropriate interventions need to be developed to improve the management of this vulnerable patient group., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background and Objectives: Risky substance use (RSU) is common among people with chronic pain and is associated with worse pain treatment outcomes. Nonopioid treatment is recommended, but it is unknown whether people with RSU use different or fewer pain treatment modalities. This study describes use of different pain treatments by veterans with and without RSU and those receiving versus not receiving opioid medication., Methods: Veterans (N = 924) who filed service-connected disability claims related to musculoskeletal conditions and rated their pain four or higher on the Numeric Rating Scale, reported on 25 different pain services in the preceding 90 days. Recent RSU was identified via Alcohol, Smoking, and Substance Involvement Test (ASSIST) cutoffs and/or nail sample toxicology., Results: Overall, RSU was not associated with number of provider-delivered or self-delivered pain modalities. Over-the-counter medications (71%), self-structured exercise (69%), and nonopioid prescription medications (38%) were the most used modalities. Veterans receiving prescribed opioids (8.4%) were more likely to see primary care, receive injections, and attend exercise and/or meditation classes, compared to those without opioid prescriptions., Discussion and Conclusions: Opioid and nonopioid pain treatment utilization did not differ based on RSU, and those prescribed opioids were more likely to engage in other nonopioid pain treatments. Regardless of RSU, veterans appear willing to try provider-delivered (58%) and self-delivered (79%) pain treatment., Scientific Significance: In this first-ever evaluation of 25 different pain treatment modalities among veterans with and without RSU, people with RSU did not use less treatment modalities., (© 2024 The American Academy of Addiction Psychiatry (AAAP).)

Background and Aims: People with opioid use disorder (OUD) commonly experience pain including chronic pain. Despite the high prevalence, few studies have systematically examined the prevalence and correlates of pain among people seeking or receiving opioid agonist treatment (OAT) for OUD. This review aimed to determine the prevalence of pain in this population globally, and estimate the association between chronic pain and other demographic and clinical characteristics., Methods: Electronic searches were conducted in three databases (Medline, Embase and PsycINFO) from the inception until October 2022. Eligible studies reported prevalence rates of current and/or chronic pain. Meta-analyses examining the main prevalence estimates were conducted by Stata SE 18.0, and comorbid clinical conditions were analysed by Review Manager 5.4., Results: Fifty-six studies (n participants = 35 267) from sixty-seven publications were included. Prevalence estimates of current and chronic pain were reported in 27 (48.2%) and 40 studies (71.4%), respectively. Most studies were conducted in North America (71.4%, n = 40) and used cross-sectional designs (64.3%, n = 36). Meta-analyses revealed a pooled prevalence of 60.0% (95% confidence interval [CI]: 52.0-68.0) for current pain and 44.0% [95% CI: 40.0-49.0] for chronic pain. Chronic pain was positively associated with older age (mean deviation of mean age: 2.39 years, 95% CI: 1.40-3.37; I 2  = 43%), unemployment (odds ratio [OR] = 0.57, 95% CI: 0.42-0.76; I 2  = 78%), more severe mental health symptoms (e.g. more severe depression (standardised mean difference [SMD] of mean scores: 0.45, 95% CI: 0.20-0.70; I 2  = 48%) and anxiety symptoms (SMD: 0.52, 95% CI: 0.17-0.88; I 2  = 67%), and hepatitis C (OR = 1.41, 95% CI: 1.03-1.94; I 2  = 0%). No association was observed between chronic pain and the onset and type of OAT, geographic location, study design, survey year, participant age or use of specific pain assessment tools., Conclusions: There appears to be a high prevalence of pain among people seeking or receiving opioid agonist treatment for opioid use disorder compared with the general population, with positive associations for older age, unemployment, hepatitis C and the severity of some mental health symptoms., (© 2024 The Author(s). Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

The use of Medicinal Cannabis (MC) for treating chronic pain is increasing, globally, yet the definition of problematic MC use remains unclear. Defining problematic use of cannabis in medical and non-medical contexts may be fundamentally different since individuals prescribed MC often experience physical dependence, which do not necessarily imply pathology. We aimed to conceptualize problematic use of MC and develop a brief questionnaire for identifying and quantifying problematic MC use. Content validation used a broad definition of problematic substance use, adapting and compiling an initial list of 36 items from various sources: (a) screening tools for assessing problematic prescription opioid medication use; (b) screening tools for problematic recreational cannabis use and (c) qualitative interviews with MC patients. 390 American self-identified chronic pain patients holding a MC card rated each item from the initial list on a 5-point frequency scale and filled out questionnaires assessing various clinical outcomes. Following initial item titration, a multi-group measurement invariance comparison strategy, using two external indicators: alcohol-related problems and depression, resulted a final eight-item list that met fit quality in a baseline model, presented excellent internal consistency reliability (α = 0.929), and significantly correlated with anxiety and low quality of life. Items in the final list related predominantly to negative consequences of MC use. Problematic use of MC is characterized by negative physiological, social, emotional and functional consequences. The final eight-item list was named the Medicinal Cannabis Negative Consequences Scale (MCNCS), emerging as a brief measure for problematic MC use and demonstrating preliminary reliability and validity, which could aid clinicians and researchers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Cannabis is used by one-third of people living with chronic pain to alleviate their symptoms despite warnings from several organizations regarding its efficacy and safety. We currently know little about self-medication practices (use of cannabis for therapeutic purposes without guidance), mainly since the legalization of recreational cannabis in countries such as Canada has expanded the scope of this phenomenon. This study aimed to describe legal cannabis self-medication for pain relief in people living with chronic pain and to explore perceptions of the effectiveness and safety of cannabis., Methods: A cross-sectional descriptive study was performed among 73 individuals living with chronic pain and using cannabis (Quebec, Canada). Data collection using telephone interviews occurred in early 2023., Results: Results indicated that 61.6% of participants reported using cannabis without the guidance of a health care professional (self-medication). Surprisingly, among those, 40.0% held a medical authorization. Overall, 20.6% of study participants were using both medical and legal nonmedical cannabis. Different pathways to self-medication were revealed. Proportion of women versus men participants self-medicating were 58.2% versus 70.6% ( P =0.284). In terms of perceptions, 90.4% of the sample perceived cannabis to be effective for pain management; 72.6% estimated that it posed no or minimal health risk., Discussion: Cannabis research is often organized around medical versus nonmedical cannabis but in the real-world, those 2 vessels are connected. Interested parties, including researchers, health care professionals, and funding agencies, need to consider this. Patients using cannabis feel confident in the safety of cannabis, and many of them self-medicate, which calls for action., Competing Interests: This project was a COPE Cohort spin-off initiative. The implementation of the cohort was supported by the Quebec Network on Drug Research and the exploitation of its data was cofunded by the Quebec Pain Research Network, 2 thematic networks of the Fonds de recherche du Québec–Santé (FRQS). In part of her masters’ degree training, C.A. (first author) received scholarships from the Canadian Consortium for the Investigations on Cannabinoids (CCIC), the Fondation de l’Université du Québec en Abitibi-Témiscamingue (FUQAT), the Fondation des Universités du Québec (FUQ), and a travel awards from the Quebec Pain Research Network (QPRN). The Chronic Pain Epidemiology Research Chair led by AL is funded by the FUQAT, in partnership with local businesses: the Pharmacie Jean-Coutu de Rouyn-Noranda and Glencore Fonderie Horne (copper smelter). The remaining authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta-9-tetrahydrocannabinol (THC). While there have been some positive findings, meta-analyses of this clinical work indicates that this effectiveness is limited and hampered by side-effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC-containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side-effects of cannabis., (© 2023 International Society for Neurochemistry.)

Shared decision-making (SDM) involving patient and physician is a desirable goal that is recommended in chronic pain management guidelines. This study measured whether SDM affects opioid prescribing frequency for chronic low back pain. A retrospective cohort study involving 1,478 participants was conducted within a national pain research registry. The patient participation and patient orientation (PPPO) scale of the Communication Behavior Questionnaire was used to measure SDM, including the classification of greater SDM (PPPO scale score ≥ 80) or lesser SDM (PPPO scale score < 80). Opioid prescribing frequency was measured at quarterly intervals from enrollment through 12 months. Baseline and longitudinal covariates were collected to adjust for potential confounding using generalized estimating equations. The mean age of participants was 53.1 (SD, 13.2) years, and 1,098 (74.3%) were female. A total of 473 (32.0%) participants were prescribed opioids at baseline. Participants completed 5,968 encounters wherein multivariable analyses demonstrated that PPPO scale scores were associated with more frequent opioid prescribing (β = .013; 95% CI, .005-.021; P < .001). Greater SDM was associated with more frequent opioid prescribing than lesser SDM (β = .441; 95% CI, .160-.722; P = .002). Opioids were prescribed in 34.3% versus 25.2% of encounters with greater versus lesser SDM (OR, 1.55; 95% CI, 1.17-2.06). SDM remained associated with more frequent opioid prescribing in a series of sensitivity analyses. Although SDM is desirable in chronic pain management, complex issues and challenging patient conversations may arise during serial assessments of the appropriateness of opioid therapy. Physicians need better education and training to address such difficult situations. PERSPECTIVE: The more frequent use of opioid therapy among patients who reported greater SDM with their physicians underscores the need for better medical education and training in dealing with the complex issues and challenges pertaining to serial assessments of the appropriateness of opioid therapy for chronic pain., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze patient and caregiver narratives addressing experiences related to substance use and substance use disorder (SUD)., Methods: Thirty audio-narratives from the MyPaTH Story Booth archive addressed substance use between 5/20/2016 and 2/24/21. Two coders established an average Cohen's kappa statistics of 0.81 over 16 stories. The primary coder coded and summarized additional narratives and conducted content and thematic analyses. The final analytic sample addressed perspectives of individuals with SUD, caregivers for individuals with SUD and individuals who have used opioids to manage pain., Results: Storytellers' average age was 51, 55 % were female and 85 % were white. Participants with SUD and caregivers described frustration with the current treatment system, reported limited treatment of SUD in medical settings, and noted relying on community-based groups for ongoing care. Individuals with chronic pain felt stigmatized and resented perceived restrictions on pain treatment due to the opioid epidemic., Conclusions: Unstructured narratives provide insights into the lived experiences of people impacted by SUD. Participants reported struggling with the effects of SUD and failing to find adequate treatment from the medical system. Stories highlight SUD-related stigma., Practice Implications: Understanding patient and caregiver perspectives related to SUD can be a critical step towards developing effective interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: A patient's perceived sensitivity to medicines (PSM) might influence the reported side effects of a treatment. The experience of side effects can result in personal and structural costs (such as nonadherence). Research on nocebo mechanisms and the workings of side effect reporting has been disproportionally smaller compared to the emerging evidence of the individual and clinical impact of the matter. In this study, we explored and re-examined the association between PSM and reported side effects within a specific population (chronic low back pain patients receiving acupuncture treatment), including possible mediating variables (i.e., gender, medical and nonmedical care utilization, optimism, pessimism, anxiety, depression and treatment expectation)., Methods: We conducted a secondary analysis of a randomized controlled trial that examined the influence of treatment outcome expectations in chronic low back pain (CLBP) patients. All measures in the analysis were self-assessments. We explored the association between PSM, reported side effects and personal characteristics using correlational and regression analyses., Results: Our sample consisted of 152 CLBP patients (65.8% female), the mean age was 39.5 years (SD = 12.5). We found positive correlations between PSM and reported side effects (r = 0.24; p < 0.01) and between PSM and anxiety (r = 0.21; p < 0.05). However, the subsequent regression analyses did not confirm a mediating or moderating effect of anxiety between PSM and reported side effects., Conclusion: We confirmed and extended earlier research on PSM. Our study involved a specific pain population receiving a nonpharmacological intervention. Our results highlight the importance of targeting PSM and anxiety within a treatment to take measures to mitigate the prevalence of side effects., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kern et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This systematic review and meta-analysis aimed to assess interventions to reduce opioid use for patients with chronic non-cancer pain (CNCP) versus usual care or active controls in primary care settings., Methods: In this registered study (PROSPERO: CRD42022338458), we searched MEDLINE, Embase PsycInfo, CINAHL, and Cochrane Library from inception to December 28th 2021, and updated on Dec 14th 2023 for randomized controlled trials (RCTs) and cohort studies with no restrictions. Methodological quality was assessed using the Cochrane Risk of Bias tool for RCTs and Newcastle Ottawa Scale for cohort studies. Primary outcomes included mean reduction in morphine equivalent daily dose (reported as mean differences [MDs] mg/day; 95% confidence intervals [95%CIs]) and/or opioid cessation proportion. Secondary outcomes were mean changes in pain severity (reported as standardized mean difference [SMDs]; 95%CIs) and (serious) adverse events. Meta-analyses were performed using random-effects models., Results: We identified 3,826 records, of which five RCTs (953 participants) and five cohort studies (901 participants) were included. Overall, opioid dosage was significantly reduced in intervention groups compared to controls (MD: -28.63 mg/day, 95%CI: -39.77 to -17.49; I2 = 31.25%; eight studies). Subgroup analyses revealed significant opioid dose reductions with mindfulness (MD: -29.36 mg/day 95%CI: -40.55 to -18.17; I2 = 0.00%; two trials) and CBT-based multimodalities (MD: -41.68 mg/day; 95%CI: -58.47 to -24.89; I2 = 0.00%; two cohort studies), respectively, compared to usual care. No significant differences were observed in opioid cessation (Odds ratio: 1.10, 95%CI: -0.48 to 2.67, I2 = 58.59%; two trials) or pain severity (SMD: -0.13, 95%CI: -0.37 to 0.11; I2 = 33.51%; three trials). Adverse events were infrequently examined, with withdrawal symptoms commonly reported., Conclusions: The studied interventions were effective in reducing opioid dosage for people with CNCP in primary care. They highlighted the importance of multidisciplinary collaboration. Large-scale RCTs measuring the long-term effects and cost of these interventions are needed before their implementation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis : cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. SIGNIFICANCE STATEMENT: Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study, we evaluated five minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that four of the five minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization., (Copyright © 2024 by The Author(s).)

Introduction: Millions of persons with chronic pain across North America and Europe use opioids. While the immunosuppressive properties of opioids are associated with risks of infections, these outcomes could be mitigated through careful patient selection and monitoring practices when appropriate. It is important to recognise that some patients do benefit from a carefully tailored opioid therapy. Enough primary studies have been published to date regarding the role of opioids in potential immunosuppression presenting as an increased rate of infection acquisition, infectious complications and mortality. There is thus a critical need for a consensus in this area., Methods and Analysis: The methodology is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies and the Cochrane Handbook for Systematic Reviews of Interventions. We plan to systematically search Ovid MEDLINE, CINAHL, PsycINFO, EMB Review, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and Google Scholar databases from their inception date to December 2023. Full-text primary studies that report measurable outcomes in adults with chronic pain, all routes of opioid use, all types of infections and all settings will be included. We will identify a scope of reported infections and the evidence on the association of opioid use (including specific opioid, dosage, formulation and duration of use) with the risk of negative infectious outcomes. Opioid use-associated outcomes, comparing opioid use with another opioid or a non-opioid medication, will be reported. The meta-analysis will incorporate individual risk factors. If data are insufficient, the results will be synthesised narratively. Publication bias and confounding evaluation will be performed. The Grading of Recommendations Assessment, Development and Evaluation framework will be used., Ethics and Dissemination: Approval for the use of published data is not required. The results will be published, presented at conferences and discussed in deliberative dialogue groups., Prospero Registration Number: CRD42023402812., Competing Interests: Competing interests: MGP is supported by the Junior-2 Salary Award from Fonds de recherche du Québec - Santé (FRQS). MJE holds a James McGill Professor Award from McGill University. BL is supported by two career awards: Senior Salary Award from the FRQS and LE 250 from the Quebec Ministry of Health for Researchers in Family Medicine. He also holds a Canadian Institutes of Health Research Strategy for Patient-Oriented Research Mentorship Chair in Innovative Clinical Trials for HIV Care. He has received research support, consulting fees and speaker fees from ViiV Healthcare, Merck and Gilead., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic pain affects one in five adults. It is not only a major cause of disability for individual patients but also a driver of costs for entire healthcare systems. Treatment of pain remains a challenge, and the use of opioids has further led to a concurrent opioid epidemic. In this review, we discuss current standard treatment options for chronic pain, including pharmacological, behavioral, and interventional treatments. In addition, we review ongoing research in different areas that will potentially unlock new therapies., Competing Interests: Declaration of interests J.W. is a cofounder and scientific advisor for Pallas Technologies, Inc., and is an inventor of a pending US patent application of pain treatment technology., (Copyright © 2024. Published by Elsevier Inc.)

Aim: This study aimed to investigate the effects of pain management according to the World Health Organization (WHO) analgesic ladder on pain severity, pain interference, and blood pressure (BP) in treated hypertensive patients with chronic musculoskeletal pain., Background: Pain management can affect BP control owing to the proposed mechanism by which persistent pain contributes to increased BP. However, there are inadequate studies investigating the benefit of pain management in controlling both pain and BP in hypertensive patients who have chronic pain., Methods: In this cross-sectional study, demographic data and pain characteristics (resting pain score on the numerical pain rating scale, pain severity, and pain interference subscale of the Brief Pain Inventory) were collected via face-to-face interviews. BP was measured thrice on the same day. Data on pain medications taken in the previous 1 month were retrieved from the medical records. Participants were categorized into three groups following pain management patterns according to the WHO analgesic ladder: no, partial, and complete treatment. Multivariate logistic regression analysis (MLRA) was used to analyse the association between the variables and uncontrolled BP., Findings: Among 210 participants, the mean (standard deviation) age was 68 (15.5) years, and 60.47% had uncontrolled BP. The resting pain score, pain severity, and pain interference subscale scores of the complete treatment group were significantly lower than that of the partial treatment group ( P = 0.036, 0.026, and 0.044, respectively). The MLRA revealed that pain management patterns were associated with uncontrolled BP (adjusted odds ratio [AOR]: 6.75; 95% confidence interval [CI]: 2.71-16.78; P < 0.001) and resting pain scores (AOR: 1.17; 95% CI: 1.04-1.38; P = 0.048). Our findings suggest that pain management patterns adhering to the WHO analgesic ladder can reduce pain severity and pain interference and also control BP in hypertensive patients with chronic musculoskeletal pain.

The development of new analgesics has been challenging. Candidate drugs often have limited clinical utility due to side effects that arise because many drug targets are involved in signaling pathways other than pain transduction. Here, we explored the potential of targeting protein-protein interactions (PPIs) that mediate pain signaling as an approach to developing drugs to treat chronic pain. We reviewed the approaches used to identify small molecules and peptide modulators of PPIs and their ability to decrease pain-like behaviors in rodent animal models. We analyzed data from rodent and human sensory nerve tissues to build associated signaling networks and assessed both validated and potential interactions and the structures of the interacting domains that could inform the design of synthetic peptides and small molecules. This resource identifies PPIs that could be explored for the development of new analgesics, particularly between scaffolding proteins and receptors for various growth factors and neurotransmitters, as well as ion channels and other enzymes. Targeting the adaptor function of CBL by blocking interactions between its proline-rich carboxyl-terminal domain and its SH3-domain-containing protein partners, such as GRB2, could disrupt endosomal signaling induced by pain-associated growth factors. This approach would leave intact its E3-ligase functions, which are mediated by other domains and are critical for other cellular functions. This potential of PPI modulators to be more selective may mitigate side effects and improve the clinical management of pain.

Chronic pain remains a significant medical challenge with complex underlying mechanisms, and an urgent need for new treatments. Our research built and utilized the iPain single-cell atlas to study chronic pain progression in dorsal root and trigeminal ganglia. We discovered that senescence of a small subset of pain-sensing neurons may be a driver of chronic pain. This mechanism was observed in animal models after nerve injury and in human patients diagnosed with chronic pain or diabetic painful neuropathy. Notably, treatment with senolytics, drugs that remove senescent cells, reversed pain symptoms in mice post-injury. These findings highlight the role of cellular senescence in chronic pain development, demonstrate the therapeutic potential of senolytic treatments, and underscore the value of the iPain atlas for future pain research., (© 2024. The Author(s).)

Abstract: Since 2000, the opioid epidemic has claimed the lives of more than 500,000 people and policies regarding the prescription of opioids for chronic pain have undergone drastic changes. While neurologists account for a small number of overall opioid prescriptions, they may treat patients on opioids, prescribed by other physicians or obtained illicitly, and need to be aware of the latest practice guidelines and the legal regime regulating opioid prescriptions., (Copyright © 2024 American Academy of Neurology.)

Aim: Evaluate the efficacy and safety ® (olokizumab) in patients with rheumatoid arthritis (RA) in real-world clinical practice, with a targeted assessment of patient report outcomes (PRO) and central sensitization., Methods: An open-label observational non-interventional study was conducted, enrolling 183 patients with moderate and severe RA activity. All patients received OKZ 64 mg SC as injections every 4 weeks (Q4W) with methotrexate. The patients' follow-up period was 24 weeks or less. RA activity (DAS28-CRP), pain severity (NRS), patient global assessment (PGA, NRS), functional impairment (NRS), fatigue (FACIT-F), central sensitization (central sensitization inventory, CSI), and symptoms of neuropathic pain (PainDETECT) were evaluated., Results: The study cohort was comprised of 144 patients. And 39 patients were lost to follow-up, refused OKZ treatment, or were not dosed with OKZ for administrative reasons. In 6 months, DAS28-CRP decreased to 3.3 ± 0.9 (p < .001) and statistically significant reductions in pain intensity, PGA, functional impairment, and fatigue were achieved. Pain intensity decreased as early as 2 days after the first OKZ administration (p < .05). The number of patients with CSI >40 in 24 weeks decreased from 71.0% to 21.0% (p < .001), with PainDETECT >18 - from 21.5% to 13.2%. NSAIDs use decreased from 70.8% to 33.8% (р < .001), steroids - from 54.2% to 32.6%. AEs were reported in 14.2% patients, serious events were observed in three patients., Conclusion: OKZ is effective in reducing RA activity and controlling chronic pain related to dysfunction of the nociceptive system., (© 2024 The Author(s). International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Opioid and cannabinoid therapies for chronic pain conditions including neuropathic pain are controversial. Understanding patient and prescribing factors contributing to risks and implementing risk mitigation strategies optimizes outcomes., Latest Developments: The ongoing transformation from a biomedical model of pain care toward a biopsychosocial model has been accompanied by a shift away from opioid therapy for pain, in particular for chronic pain. Opioid overdose deaths and opioid use disorder have greatly increased in the last several decades, initially because of increases in opioid prescribing and more recently associated with illicit drug use, in particular fentanyl derivatives. Opioid risk mitigation strategies may reduce risks related to opioid prescribing and tapering or discontinuation. Opioid therapy guidelines from the Centers for Disease Control and Prevention have become the consensus best practice for opioid therapy. Regulatory agencies and licensing medical boards have implemented restrictions and other mandates regarding opioid therapy. Meanwhile, interest in and use of cannabinoids for chronic pain has grown in the United States., Essential Points: Opioid therapy is generally not recommended for the chronic treatment of neuropathic pain conditions. Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions (such as postherpetic neuralgia), and only as part of a multimodal treatment regimen. Opioid risk mitigation strategies include careful patient selection and evaluation, patient education and informed consent, querying the state prescription drug monitoring programs, urine drug testing, and issuance of naloxone as potential rescue medication. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required. There is evidence for the efficacy of cannabinoids for neuropathic pain, with meaningful response rates in select patient populations., (Copyright © 2024 American Academy of Neurology.)

Tapentadol is a unique opioid analgesic due to its dual mechanism of action. Compared to other opioids with a classical mechanism of action, its analgesic potential is not far behind them, and its advantages are: a better safety profile in terms of a lower potential for drug-drug interactions and a lower potential for causing adverse events, and it is safe to use in sensitive populations. Tapentadol in the form of a immediate release formulation is an adequate drug of choice for achieving a pharmacotherapeutic analgesic response in acute pain conditions, while in the form of a extended release formulation it is an adequate pharmacotherapeutic analgesic solution for chronic pain syndromes of various etiology. Due to the specificity of the mechanism of action, tapentadol adequately relieves both pain components - nociceptive and neuropathic, and has an indication area for mixed pain syndrome as well. Based on this, the need for the use of co-analgesics is reduced, and thus the incidence of possible interactions and adverse events is reduced.

Importance: Centers for Disease Control and Prevention guidelines advocate reduced opioid prescribing for chronic pain, yet research on their implementation remains limited., Objective: To compare 4 deimplementation strategies to promote guideline-concordant opioid prescribing., Design, Setting, and Participants: This cluster randomized clinical trial was performed at 32 primary care clinics from 2 US health care systems from February 2020 to March 2022, using a hybrid type 3 sequential multiple-assignment design focused on patient outcomes. Clinics were recruited through volunteer sampling, including 268 clinicians and 8978 patients. Data were analyzed from September 2020 to March 2022., Intervention: Deimplementation strategies were targeted at the system, clinic, and prescriber levels. All clinics received a system-level strategy consisting of quarterly educational meetings with monthly audit and feedback (EMAF) reports. At month 3, half the clinics were randomized to receive practice facilitation (PF), a clinic-level strategy that targets clinic workflows. At month 9, half the clinics were again randomized to add prescriber peer consulting (PPC), a prescriber-level strategy focused on challenging patient cases., Main Outcomes and Measures: The primary outcome was change in mean morphine milligram equivalent (MME) dose in clinics receiving the least intensive bundle of deimplementation strategies (EMAF) vs the most intensive (EMAF plus PF plus PPC). Secondary outcomes included adherence to guideline metrics aimed at mitigating opioid risk., Results: Among the 8978 patients included in the analysis, 5142 (57.3%) were female; 42 (0.5%), American Indian or Alaska Native; 74 (0.8%), Asian or Pacific Islander; 411 (4.6%), Black; 187 (2.1%), Hispanic or Latino; 8127 (90.5%), White; and 137 (1.5%), other or unknown. Mean (SD) age was 58.3 (14.3) years. Eight clinics (including 66 prescibers and 2044 patients) assigned the most intensive strategy (EMAF plus PF plus PPC) had statistically significant effects on the primary outcome compared with 7 clinics (including 60 clinicians and 2427 patients) receiving the least intensive strategy (EMAF); clinics in the high-intensity group decreased the mean MME dose by 2.4 (95% CI, -4.3 to -0.5) mg/d more than the EMAF group (P = .02), representing a 6% reduction, and increased screening for pain severity, enjoyment of life, and general activity by 5.4% (95% CI, 0.4%-10.4% [P = .04]) more. Compared with EMAF, the most intensive strategy resulted in statistically significant decreases in urine drug screening (difference, -7.3% [95% CI, -11.5% to -3.0%]; P < .001) and use of treatment agreements (difference, -6.7% [95% CI, -11.1 to -2.3%]; P = .003), in the opposite direction of the hypothesis. There were no significant differences between groups in benzodiazepine coprescribing, mental health screening, or patients receiving an MME dose greater than or equal to 90.0 mg/d., Conclusions and Relevance: In this cluster randomized clinical trial, a high-intensity deimplementation strategy targeted at prescribers significantly decreased the MME dose and increased screening for pain intensity and pain-related interference while reducing use of treatment agreements and urine drug screening. Providing clinic- and prescriber-level deimplementation strategies may help health systems take positive steps toward reducing reliance on opioid medications for chronic pain management in primary care settings., Trial Registration: ClinicalTrials.gov Identifier: NCT04044521.

Background: Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown., Objective: To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal., Design: This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682)., Setting: We analysed trials from all settings., Participants: We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache., Interventions: We included all antidepressants., Main Outcome Measures: Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial., Results: We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled ( n = 83) and parallel armed ( n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain., Limitations: The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects., Conclusions: There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety., Future Work: There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance., Study Registration: This study is registered as PROSPERO CRD42020171855., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment ; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

Background: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression., Methods: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior., Results: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice., Conclusions: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Competing Interests: The authors declare no conflicts of interest.